A PRELIMINARY INVESTIGATION OF THE MECHANISMS UNDERLYING CANNABINOID TOLERANCE IN THE MOUSE VAS-DEFERENS

Vasa deferentia taken from mice treated with Delta(9)-tetrahydrocannabinol (20 mg/kg i.p., once daily for 2 days) showed tolerance to the inhibitory effect of the cannabinoid, R-(+)-arachidonyl-1'-hydroxy-2'-propylamide, on electrically evoked twitches. This treatment did not induce tolerance to the inhibitory effects on the twitch response of morphine or clonidine or of selective mu-, delta- or kappa-opioid receptor agonists. Nor did it affect the contractile potencies of noradrenaline or beta,gamma-methylene-L-ATP. We suggest that cannabinoid tolerance in the vas deferens is attributable neither to downregulation of opioid receptors or alpha(2)-adrenoceptors nor to an increased sensitivity of this tissue to its main contractile transmitters noradrenaline and ATP. A concentration of Delta(9)-tetrahydrocannabinol that inhibits electrically evoked twitches of the vas deferens (100 nM) did not alter the ability of noradrenaline or beta,gamma-methylene-L-ATP to induce contractions suggesting that Delta(9)-tetrahydrocannabinol inhibits the twitch response by acting prejunctionally.